Comment on Mansouri et al, page 1932
In this issue of Blood, Mansouri and colleagues show that in addition to suppressing expression of histocompatibility complex class I molecules, the K5 gene product of KSHV also targets CD31. It does this by 2 separate mechanisms, one that targets newly synthesized CD31 and one that targets CD31 already expressed on the cell surface.
The interactions between viruses and their hosts are often quite complex. This is especially true with gamma-herpesviruses such as Kaposi sarcoma–associated herpesvirus (KSHV) and other viruses that persist in a latent state. Two KSHV-encoded genes, K3 and K5, have previously been shown to target major histocompatibility complex class I (MHC I) and related molecules,1-3 and thus serve to protect KSHV-infected cells against immune attack. Mansouri and colleagues now find that K5, but not K3, also targets CD31. As revealed in an elegant series of experiments, K5 destroys newly synthesized CD31 in endothelial cells by a process that involves ubiquitinization and proteosomal degradation. This process involves the binding of phosphofurin acidic cluster sorting protein-2 (PACS-2) to K5. At the same time, K5 destroys preexisting surface CD31 molecules by a process that involves endocytosis, ubiquitinization, and lysosomal degradation. Thus, K5 attacks use a 2-pronged approach, targeting both newly synthesized and preexisting CD31 molecules.
Specific viral genes often modulate host-cell functions in ways that benefit the virus. It is not difficult to envision the evolutionary advantage to KSHV of targeting MHC I. But why CD31? CD31, a member of the immunoglobulin supergene family, is highly expressed on endothelial cells and is involved in the formation of cell-to-cell contacts. Recent studies have shown that it can also act as a scaffold molecule for a number of signaling pathways and is involved in a wide range of biological functions such as leukocyte transmigration, angiogenesis, regulation of apoptosis, and monocyte chemotaxis.4 It remains unclear which functions of CD31 are most important for KSHV to block. One possibility is that targeting CD31 makes cells producing KSHV more likely to break away and disseminate the virus.
The ability of gamma-herpesviruses to modulate the host cell can also promote the formation of tumors. KSHV, also called human herpesvirus-8 (HHV-8), is the causative agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). The induction of such tumors, however, is best viewed as a biological accident, and not every viral gene or gene function necessarily serves to promote tumorigenesis. K5 is expressed in KS, PEL, and MCD,2 and it is likely that the down-regulation of MHC I by this gene helps these tumors avoid immunologic control. It is unclear, however, whether the targeting of CD31 promotes tumorigenesis. As suggested by Mansouri and colleagues, it is possible that the reduction of bonds between endothelial cells by K5 facilitates the spread of KS cells throughout the body. Additional research will be needed to explore this and other possibilities. Whatever its benefit to the virus, K5 has shown a remarkable ability to target CD31 by 2 separate mechanisms. Learning more about this process will help inform our understanding of protein trafficking in cells, and may also provide new insights into the KSHV life cycle and its ability to induce tumors.
This commentary was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
Financial disclosure statement: The senior author (R.Y.) and/or his spouse are coinventors on one or more United States government patents (or outstanding patent applications) that include anti-HIV therapies, peptide vaccine therapy for HIV and other viruses, antiangiogenic compounds, an assay for viral interleukin-6 of KSHV, and interleukin-12 as a treatment for Kaposi sarcoma. These inventions were all made as full-time employees of the United States government under 45 Code of Federal Regulations Part 7. All rights, title, and interest to these patents has been assigned to the United States government. The government conveys a portion of the royalties it receives to its employee-inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). ▪